Delivery device

ABSTRACT

An active principle delivery device ( 1 ) comprising an inner capsule ( 4 ) within an outer capsule ( 2 ), the inner and outer capsules ( 4, 2 ) containing the same active principle ( 5, 3 ), with at least the outer capsule ( 2 ) being a hard capsule and the active principle ( 3, 5 ) in at least one of the capsules ( 2, 4 ), comprising a fluid. Also provided is a method of fabricating such a delivery device ( 1 ), as well as a method of controlling the pharmaco-kinetic profile of an active principle.

[0001] This invention relates to a delivery device and a method ofdelivering a substance to at least one location, more particularly theinvention relates to a delivery device comprising one or more capsuleswithin an outer capsule, with at least two of said capsules containingthe same active principle and a method of delivering that activeprinciple.

[0002] Capsule technology has been developing for over one hundred yearsand is now at the stage where many medicaments are formulated so as tobe encapsulated within a gelatin capsule. The benefits of suchformulations reside in the fact that the capsules are often easy for apatient or other consumer to swallow or use and the capsule can containa large amount of the particular medicament for delivery to theindividual, the actual capsule dissolving in the stomach or other partof the intestinal tract.

[0003] Indeed, to ensure that a particular medicament is delivered tothe desired site, a large amount of research has been carried out incoating techniques. Such techniques are used to control or at least varythe time or location of dissolution of the capsule and, consequently,the time or location of release of the medicament.

[0004] Several known techniques have been developed for theadministration of more than one active principle at a time or at shortintervals whilst the active principle is in tablet form. In those cases,coatings are also used to vary or control the release time or locationof that active principle.

[0005] U.S. Pat. No. 1,815,902 (Ellzey) discloses a double capsule, withone capsule within the other, for administering medicaments in which aninner hard gel capsule contains medicament, whilst an outer hard gelcapsule contains an innocuous alkaline material.

[0006] FR 1454013 (Pluripharm) relates to another type of double capsulewith different medicaments, in solid form, in the inner and outercapsules which are made of hard gel, whilst DE 2729068 (Liedtke) isdirected to a double capsule in which the same or different activeprinciples in solid form are provided in inner and outer hard gelcapsules, with any liquids being provided solely in inner and outer softgel capsules.

[0007] In FR 2524311 (Azalbert), there is described another doublecapsule for the ingestion of medicinal agents which are different andincompatible with one another. The inner and outer capsules are of hardgel, with the medicinal agents possibly being in liquid form.

[0008] EP 0116311 (Morishita Jintan Co et al) teaches a double soft gelcapsule with the inner and outer capsules containing differentmedicines, whilst EP 0130163 (Pharmacia) discloses a double capsule withthe inner capsule containing an allergen and the outer capsulecontaining an antiallergie substance.

[0009] U.S. Pat. No. 5,310,555 (Zimmer) is directed to a method ofdelivering incompatible and different compounds in vivo, with liveintestinal or rumen microorganisms in an inner capsule and a nutritionalsupplement in an outer shell in which the inner capsule is contained.

[0010] EP 0624365 (ASTA Medica) describes a form of double capsulearrangement in which an outer sheath has bioadhesive properties andcontains a capsule containing at least one hygroscopic substance andnon-liquid active agent tablets.

[0011] WO 95/10262 (RP Scherer Corporation) relates to a controlledrelease device for delivering a liquid substance to a patient, whereindifferent materials are contained in a double capsule. The liquidsubstance is contained in an inner soft or hard gel capsule and an inertsolid excipient is contained in an outer hard gel capsule, with awater-swellable material in the outer capsule for causing disengagementof the capsules upon exposure to an aqueous medium.

[0012] WO 99/30693, AXCAN PHARMA shows that it is possible to provide adouble capsule for the administration of active medicaments in multipletherapies. This disclosure considers the possibility of treating amicroorganism, such as Helicobacter pylori, with known solid medicamentsin a double capsule.

[0013] The multiple capsule delivery devices discussed above show thatis known to provide double, triple and, sometimes, quadruple therapiesfor the treatment of many conditions, wherein the inner and outercapsules can be provided in certain, but not all, combinations of solidand soft get capsules containing the same or different active principlesin solid or liquid form.

[0014] However, none of the prior art delivery devices discussed aboveever discloses, whether directly or by implication, the use of the sameactive principle as a fluid, such as liquid or semi-solid, in aparticular multiple capsule format for the treatment of a plurality ofconditions.

[0015] Also, these known multiple capsule delivery devices providetreatment regimes which are limited, as it has been found to bedifficult to control and vary the posologies, particularly when solidactive principles are employed. Indeed, it is known also that certainactive principles are not amenable to patients in solid form and it iswell established that the most effective dose of most medicaments occurswhen the active principles are in liquid form, for example, as anaqueous solution, suspension, micelle or emulsion.

[0016] Accordingly, it is an object of the invention to provide adelivery device which overcomes the problems associated with the knowndevices of the prior art discussed above. It is also an object toprovide a delivery device which can be used in the treatment of aplurality of conditions, where at least one desired form of activeprinciple is fluid and where it is desired to control both the releaserate and site of release of the active principle.

[0017] Thus, a first aspect of the invention provides an activeprinciple delivery device comprising an inner capsule within an outercapsule, wherein:

[0018] the inner and outer capsules contain the same active principle;

[0019] at least the outer capsule is a hard capsule; and

[0020] the active principle in at least one of the capsules comprises afluid (as hereinafter defined).

[0021] A second aspect of the invention resides in a method offabricating an active principle delivery device, comprising:

[0022] providing a first capsule and a second capsule of which at leastthe first capsule is a hard capsule;

[0023] placing the same active principle in each of the first and secondcapsules, with the active principle in at least one of the capsulescomprising a fluid (as hereinafter defined); and

[0024] placing the second, active principle-containing, capsule withinthe first, active principle-containing, hard capsule.

[0025] In a third aspect of the invention, there is provided a method ofcontrolling the pharmaco-kinetic profile of an active principlecomprising:

[0026] determining the most efficacious site of active principlerelease;

[0027] placing an active principle in a first hard capsule;

[0028] placing the same active principle in a second capsule within theactive principle-containing, first hard capsule, with the activeprinciple in at least one of the first and second capsules comprising afluid (as hereinafter defined), to provide a delivery device;

[0029] delivering the delivery device to the predetermined activeprinciple release site; and

[0030] controlling the release of the active principle at the site.

[0031] In preferred embodiment to be described hereinbelow, the activeprinciple is medicinal and/or nutritional.

[0032] Throughout this specification, the term “fluid” or derivativesthereof is used to describe a material which is a liquid or a semi-solidbut not a gas, a liquid being defined as a material which flows underambient conditions without external influences, whilst a semi-solid isdefined as a material or mixture of material which has a consistencythat varies according to its conditions within an ambient range andwhich may have characteristics of both a liquid and a solid. Examples ofsemi-solids include creams, pastes, ointments, suspensions, emulsions,thixotrope and waxes. Changes in ambient conditions, such as atemperature change, could alter a semi-solid to a more liquid state,whilst agitation, such as shaking, could change a thixotrope from a moresolid state to a more liquid state.

[0033] At least a portion of the active principle may be a fluid eitherat or immediately prior to its time of use or during its manufacture

[0034] Although the first, outer capsule is a hard capsule, the second,inner capsule may be a hard or soft capsule and each may be constructedfrom, for example, gelatin, plasticised gelatin, hydroxy propyl methylcellulose (HPMC), starch or agar. Each of the inner and outer capsulesmay be coated or uncoated. In a preferred embodiment, the second innercapsule is a hard capsule and the active principle in both the inner andouter capsules comprises a fluid.

[0035] Preferably, the fluid is a liquid which may be a solution orsuspension and may comprise suspended solids which may be a powder,pellet, or granules and which may be coated or uncoated. The liquid mayalso be thermosoftening. At least one of the capsules may contain thesame active principle in more than one phase, for example, liquid,semi-solid and/or solid phases.

[0036] The delivery device may comprise more than one second, innercapsule within the first, outer capsule, the second, inner capsulesbeing arranged in parallel and/or in series.

[0037] In a preferred embodiment, the delivery device provides apharmaceutical dosage form for the administration of the same activeprinciple in single therapies.

[0038] Also, the device may comprise an activator or co-reactant for theactive principle.

[0039] The various aspects of the invention will now be described by wayof example only, and with reference to the accompanying drawings inwhich:

[0040]FIG. 1 is a section through a first embodiment of delivery device;

[0041]FIG. 2 is a section through a second embodiment of deliverydevice;

[0042]FIG. 3 is a section through a third embodiment of delivery device;and

[0043]FIGS. 4A to 4D are example representations of pharmaco-kineticprofiles.

[0044] Referring firstly to FIG. 1, a double capsule delivery device,indicated generally at 1, comprises a first, outer hard capsule 2containing a liquid active principle 3 and a second, inner hard capsule4 which also contains the same liquid active principle 5 as thatcontained in the outer hard capsule 2 and may be coated, as shown at 6.

[0045] Similarly, FIG. 2 illustrates a triple capsule delivery device,indicated generally at 11, which comprises a first, outer hard capsule12 containing a liquid active principle 13 and a second, inner hardcapsule 14 which also contains the same liquid active principle 15 asthat contained in the outer hard capsule 12 and may be coated, as shownat 18. The second, inner hard capsule 14 also contains a third, innerhard capsule 16 which, in turn, contains the same active principle asthat contained in the first and second, outer and inner hard capsule 12and 14 but in solid particulate form. That second, inner hard capsule 14may also be coated, as shown at 19. The capsules 12, 14 and 16 are inseries with each other.

[0046] Referring now to FIG. 3, a multiple capsule delivery device,indicated generally at 21, comprises a first, outer hard capsule 22containing a liquid active principle 23 and four inner hard capsules 24containing an active principle 25 which is the same as that contained inthe first, outer capsule 22 but in semi-solid form. The four innercapsules 24 are in parallel with each other but in series with the outercapsule 22.

[0047] Each capsule 2, 4, 12, 14, 16, 22, 24 may be filled usingstandard capsule-filling technology, such as intermittent or continuousmotion capsule filling machines equipped with dosators, to place thesame active principle therein. Similar technology may be used to placethe inner capsules 4, 14, 16, 24 within the respective outer capsules 2,12, 22.

[0048] Although the first outer capsule 2, 12, 22 is a hard capsule, asare the inner capsules 4, 14, 16, 24 in the three embodiments describedabove, the inner capsules 4, 14, 16, 24 may be soft capsules. However,any combination of hard and soft inner capsules may be employed. Also,although the first, outer hard capsule 2, 12, 22 of those threeembodiments contains the active principle as a liquid, it need notnecessarily, as long as at least one of the outer capsules 2, 12, 22 andthe inner capsules 4, 14, 16, 24 contains the active principle as aliquid.

[0049] The outer hard capsule 2, 12, 22 may be made from any suitablematerial which will depend upon application requirements. Such materialsmay include hard gelatin, hydroxy propyl methyl cellulose (HPMC) andstarch, whilst any inner 1o capsule 4, 14, 16, 24 which is hard may bemade from such a material. Alternatively, and if any inner capsule is asoft capsule, then such may be made from soft gelatin or agar.

[0050] It is well established in the medical treatment of ailments, inparticular, human ailments, that there are two important thresholds fordrugs. The first threshold is the therapeutic threshold, which may bedefined as the concentration of active principle at which the principleshows a therapeutic effect on the particular ailment. The second suchthreshold is the toxic threshold, which occurs when the amount of drugreaches a concentration at which the person who has ingested the drugis, or at least starts to become, poisoned thereby. This effectiveconcentration range between the therapeutic and toxic thresholds may bedefined as the activity window.

[0051] Active principles, once released, are normally absorbed by thebody where they are either metabolised or excreted. Obviously, thebalance between release/absorbance rate and removal rate (for example,the sum of the rates of excretion and metabolisation) provides theso-called pharmaco-kinetic profile of a particular active principle. Thepharmaco-kinetic profile for a particular active principle may benon-ideal. For example, the concentration of active principle at thedesired site may rapidly fall below its therapeutic threshold oncereleased. Alternatively, and as is more usual, the concentration of thedrug may slowly reduce to below the therapeutic threshold beforesufficient time has elapsed for the active principle to yield thedesired result.

[0052] A solution to this low active principle concentration problem issimply to administer more of the active principle. However, whilst thismay increase the concentration of the active principle and concomitantlythe time that the patient's blood contains above the therapeuticthreshold, it may also increase the concentration above the toxicthreshold, consequently poisoning the person to whom the drug wasadministered. Indeed, some active principles have very small activitywindows and therefore administering large doses of the active principleis undesirable. In such cases, it is usual to prescribe complicatedadministration regimes wherein a patient is forced to take a largenumber of relatively small dose drugs frequently. Such regimes arecostly and difficult to administer, act to limit or control thepatient's freedoms and, moreover, may be difficult to ensure patient'scompliance therewith.

[0053] With regard now to FIG. 4A, there is shown a pharmaco-kineticprofile W of active principle concentration against time for aparticular active principle. The curve W is found after administrationof an active principle, in a single therapy, in the form of the deliverydevice 1, shown in FIG. 1.

[0054] The delivery device 1 comprises the outer hard capsule 2 whichcontains the liquid active principle 3 and which is uncoated and theinner capsule 4 which also contains the same liquid active principle 5and which is provided with an enteric or erodible coating 6. Onceingested, represented by R₁, the outer capsule 2 is quickly broken downand the contents 3 made available, showing an increase in theconcentration of the active principle. The coating 6 on the innercapsule 4 prevents immediate release of the contents 5 thereof. However,over time the coating breaks down and, at R₂, the contents 5 arereleased and therefore made available to the body. The effect, as shownin FIG. 4A, is a superposition of two active principle concentrationcurves to provide the composite pharmaco-kinetic profile W shown.

[0055] In FIG. 4A, the active principle 3, 5 has a relatively longabsorption half-life, which is to say that it is slowly absorbed by thebody. In contrast, FIG. 4B shows a situation wherein the activeprinciple 3, 5 has a short absorption half-life and is rapidly absorbed(and eliminated) by the body. A delivery device 1, such as that shown inFIG. 1, may be used and again, the inner capsule 4 is coated at 6 toprevent early release of the active principle 5 contained therein. Ascan be seen in FIG. 4B, the superposition of the two active principleconcentration curves provides a composite pharmaco-kinetic profile Xshowing the pulsed release of the principle 3, 5. The activity window AWof the same principle 3, 5 is also indicated (AW=toxic threshold(To)−therapeutic threshold (Th)). Such a formulation, as is containedwithin the delivery device 1, allows for continual administration of anefficacious dose whilst the patient only has to take a single capsule.

[0056] Obviously, a delivery device 11 such as that shown in FIG. 2could also be configured to provide pulsed release of a principle. Insuch a device 11 the intermediate capsule 14 may be coated at 18 toprevent immediate release, as may the inner capsule 16 at 19, the effectbeing a “three-pulse” system in which the active principle 13, 15, 17 isdelivered, or at least made available, in a controlled fashion.Moreover, with a surreptitious choice of coatings 18, 19, a so-called“parallel” device 21 as shown in FIG. 3 could also be used.

[0057]FIG. 4C shows a composite pharmaco-kinetic profile Y in whichsustained release of the active principle is described. The deliverydevices 11, 21 may be arranged to provide such a profile Y. In somecases, a large dose of a principle is required although the body may notrespond positively to a large immediate dose. Thus the active principleconcentration is “ramped-up” slowly by sequential release of activeprinciple from sequential breakdown of the capsules. In FIG. 4C, threereleases R₂₁, R₂₂, R₂₃ are indicated. With certain medicaments, thetoxicity threshold To may increase once the body has adjusted to theinitial dose. In such circumstances, it is beneficial to providesequential release of the active principle, taking advantage of thepatient's increased tolerance thereof.

[0058]FIG. 4D shows a representation of a further compositepharmaco-kinetic profile Z in which two releases R₃₁, R₃₂ are indicated.The first release R₃₁ shows a rapid rise in active principleconcentration which equally rapidly dies away, the second release R₃₂providing a sustained release of active principle. This matched acuteand chronic release profile provides a composite pharmaco-kineticprofile Z in which the patient is exposed to a large initialconcentration of active principle followed by a sustained increase inactive principle concentration. Such a profile Z may be desirable incircumstance where the initial dose primes the patient for a moresustained dose. Both serial and parallel devices 1, 11, 21 may beutilised to provide such a profile, with careful consideration beinggiven to the choice of coatings 6, 18, 19 which could be applied to anyor all of the capsules 2, 4, 12, 14, 16, 22, 24.

[0059] The FIGS. 4A to 4D show particular pharmaco-kinetic profiles W,X, Y and Z. It will be understood by the skilled addressee that manydesired profiles are achievable. For example, it is a simple matter toprovide, or at least closely approximate, a steady-state activeprinciple concentration, which is to say an invariant pharmaco-kineticprofile over time, the rate of removal being equal to the rate ofrelease/absorption of active principle. In such a fashion, thegastrointestinal (GI) tract, or at least a portion thereof, may besubjected to an at least approximately constant concentration of activeprinciple as a delivery, device 1, 11, 21 travels therealong, releasingits active principle. Alternatively, a certain portion of the GI tractmay be subjected to a steady-state concentration whilst another portionis subjected to a pulse of active principle, for example.

[0060] The above discussion has been silent as to the most efficacioussite of principle delivery. The delivery devices 1, 11, 21 can be usedto deliver their contents to the most efficacious site in thegastrointestinal (GI) tract. For example, certain active principles maynot be best suited for uptake from the acidic conditions prevalent inthe stomach and may be best suited for up-take in the colon. In suchcircumstance the capsules can be coated such that they are only slowlydissolved under strongly acidic conditions, thereby bypassing thestomach.

[0061] Moreover, it may be desirable to deliver an active principle tomore than one site in the GI tract, for example the stomach and thecolon. For such a delivery regime, the inner capsule 4 may be providedwith a coating which slowly dissolves once exposed to the conditions ofthe stomach, the outer capsule 2 having been dissolved soon afteringestion. In this case, the coating is arranged to dissolve, under theprevailing conditions, in the time taken for the device 1 to travel fromthe stomach to the desired delivery site. A typical release profile maybe shown by the pharmaco-kinetic profile Z of FIG. 4D in which the firstrelease R₃₁ occurs in the stomach and the second release R₃₂ occursfurther down the GI tract, for example in the colon. As is shown, theactive principle concentration in the stomach and colon of the activeprinciple are distinct due to the differing environmental conditions,the desired treatment regime and the efficacy of the active principle ineach location.

[0062] An example of the potential uses of such a regime is in thetreatment of excess dissolved intestinal gases. Intestinal wind is, inthe main, caused by the swallowing of air whilst eating and drinkingtogether with the small amount which is formed through the bi-productsof bacterial digestion within the stomach and GI tract. These gasesbecome dissolved in the stomach contents and can cause discomfort, insome cases pain, and embarrassment. The usual way to treat such anailment is to provide medicaments such as simethicone or dimethiconewhich reduce the surface tension of the stomach GI tract contents,allowing the dissolved gases to come out of solution and be releasedfrom the body. Whilst the problem of dissolved gases can be addressed inthe stomach it is conventionally relatively difficult to treat theproblem lower in the GI tract without using high doses. The deliverydevice 1 may be used to do so, in the manner discussed above with alower dose of the active principle.

[0063] A further method of altering the release rate, and thus theabsorbance profile, of an active principle, is to provide the sameactive principle in a two or more different and distinct phases, forexample solid and liquid within a single capsule. For example, thedelivery device 1 of FIG. 1 may comprise an uncoated outer capsule 2 inwhich is situated a liquid active principle 3 and a coated inner capsule4. The inner capsule 4 may contain the same active principle 5 in, forexample, an aqueous liquid formulation and a coated solid, such aspellet, formulation. The encapsulated active principle could also bethermosoftening, which is to say that as the temperature increases theviscosity of the active principle decreases.

[0064] Once the outer capsule 2 has dissolved and the contents 3 thereofhave been absorbed, the inner capsule 4 starts to dissolve. Once thishas occurred the aqueous liquid formulation of the active principle 5 israpidly absorbed whilst the coating on the pellets is dissolving. Asthat coating dissolves, the solid formulation of the active principle isabsorbed by the patient providing a double pulse and sustained releasecomposite pharmaco-kinetic profile.

[0065] Such delivery devices 1; 11; 21 may also be used to separateimmiscible components. For example, in certain therapies it isbeneficial to deliver the same active principle in a variety ofsolvents. Such solvents may be water and lipids or fats, the innercapsule 4 containing, for example, an aqueous liquid formulation of theactive principle 5 and the outer capsule 2 containing a lipidicformulation of the same active principle 3. These same principles 3, 5may be delivered to the same or different sites within the body as thetreatment necessitates and which delivery sites may be controlled by acoating on the capsules 2, 4.

[0066] Thus, it can be seen that with an adroit choice of coating and/orby consideration of the capsules dissolution profile, which is to saythe rate at which the capsule dissolves, the delivery device 1; 11; 21can be arranged to provide the desired pharmaco-kinetic profile fortreatment of a particular ailment. This can also be augmented by theprovision of the same active principle in a particular phase or inparticular phases within each capsule. The provision of serial andparallel arrangements of capsules within a delivery device may also beutilised to control or vary the release of active principle.

[0067] In further embodiments, the delivery device, for example 1, maycomprise further active principles together with the same primaryprinciple. For example, the outer capsule 2 may contain a main activeprinciple 3 together with another, second active principle, whereasinner capsule 4 may contain the same main active principle 5 and afurther, third active principle, main principles 3 and 5 being the samein the same or different phases. The above-identified second and thirdactive principles may inhibit each others activity or it may bedesirable to treat a different site within the GI tract with each orthey may act synergistically in an undesired fashion. The deliverydevice 1 affords a clinician the ability to provide all three principlesin one delivery device, whilst pre-determining the active principlerelease profiles and the site of release. This leads to directedtreatment of one or more specific ailments, allowing medical staff toaccurately target delivery sites and ensure that the active principleconcentration is optimum.

[0068] It is known that different shell materials exhibit a wide-rangeof properties. For example, gelatin capsules show an excellentresistance to oxygen penetration but are readily embrittled by the lossof moisture therefrom. However, HPMC capsules are readily penetrated byoxygen whilst being very resistant to moisture embrittlement. Therefore,an oxygen sensitive active principle could be encapsulated within aninner gelatin capsule 4 which is in turn encapsulated within an outerHPMC capsule 2 containing, for example, a non oxygen sensitiveformulation. The HPMC outer capsule 2 provides a flexible tough outershell whilst the brittle inner gelatin capsule 4, which is protected bysupport from the surrounding active principle, provides protectionagainst oxidation of its contents.

[0069] It has been demonstrated that the delivery devices 1; 11; 21allow for a flexibility of delivery of an active principle. By a simplechoice of capsule materials, together with manipulation of capsulecoating and or formulation of the active principle it is possible toaccurately and precisely target active principle delivery site andconcentration. It also allows for incompatible substances to beseparated until such times as they are released or, indeed, to keepsubstances completely separated, delivering said principles to distinctsites.

[0070] Moreover, it allows for the simplification of a treatment regime.The delivery devices 1; 11; 21 provide means for controlling complicatedtreatment regimes and removing some or all of the onus from the patient.In some therapies, cocktails of drugs are prescribed which have to betaken at set times, after meals for example, or in pre-determinedpatterns. Use of the inventive delivery devices 1; 11; 21 allows fordrastic simplification of that procedure which may have profound effectsin, for example, rural locations of developing countries where literacyrates may be low and clinicians are not on hand to supervise everyaspect of a patient's treatment.

[0071] Moreover, in the treatment of animals such simplification ofadministration regimes is desired. For example, it may be difficult orarduous to repetitively administer medicaments to animals to treat aparticular complaint. The inventive delivery devices 1; 11; 21 providemeans to simplify that procedure, ensuring that the animal receives thedesired dose of medicament whilst minimising the number of times a vet,for example, has to visit the animal and simplifying the treatmentregime.

[0072] In, certain medical or other uses, time and one or moreprevailing environmental conditions may affect the release rate. Forexample, the acidity of the stomach may partially control the releaserate.

[0073] It is clear, therefore, that the inventive delivery devices 1;11; 21 and associated methods provide means of delivering activeprinciples and other components to a desired site by control of a fewsimple parameters. It should be understood that although the inventionhas been described with reference to the above examples, the ambit ofthe invention is to be determined by the appended claims.

[0074] It is to be appreciated that certain features of the invention,which are, for clarity, described in the context of separateembodiments, may also be provided in combination in a single embodiment.Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any suitable sub-combination.

1. An active principle delivery device comprising an inner capsulewithin an outer capsule, wherein: the inner and outer capsules containthe same active principle; at least the outer capsule is a hard capsule;and the active principle in at least one of the capsules comprises afluid (as hereinbefore defined)
 2. A delivery device according to claim1, wherein at least a portion of the active principle is a fluid eitherat or immediately prior to its time of use or during its manufacture. 3.A delivery device according to claim 2, wherein the fluid is a liquidwhich comprises a solution and/or a suspension of the active principle.4. A delivery device according to claim 3, wherein the liquid isthermosoftening.
 5. A delivery device according to any of claims 1 to 4wherein at least the outer capsule comprises gelatin, plasticisedgelatin, hydroxy propyl methyl cellulose (HPMC), starch or agar.
 6. Adelivery device according to any of claims 1 to 5, wherein at least oneof the inner and outer capsules is coated or uncoated in accordance witha desired release profile of active principle.
 7. A delivery deviceaccording to any preceding claim, wherein the active principle comprisesa fluid suspended solid.
 8. A delivery device according to claim 7,wherein the fluid-suspended solid comprises a powder, a pellet, granulesor any combination thereof.
 9. A delivery device according to claim 7 or8, wherein the fluid suspended solid is coated or uncoated in accordancewith a desired release profile of active principle.
 10. A deliverydevice according to any preceding claim, wherein at least one of theinner and outer capsules contains the active principle in more than onephase.
 11. A delivery device according to any preceding claim comprisingmore than one inner capsule within the outer hard capsule, the innercapsules being arranged in parallel and/or in series.
 12. A deliverydevice according to any preceding claim which provides a pharmaceuticaldosage form for the administration of the same active principle insingle therapies.
 13. A delivery device according to any precedingclaim, wherein the active principle comprises a medicinal or nutritionalproduct.
 14. A delivery device according to any preceding claim furthercomprises an activator or co-reactant for the active principle.
 15. Amethod of fabricating an active principle delivery device, comprising:providing a first capsule and a second capsule of which at least thefirst capsule is a hard capsule; placing the same active principle ineach of the first and second capsules, with the active principle in atleast one of the capsules comprising a fluid (as hereinbefore defined);and placing the second, active principle-containing capsule within thefirst, active principle-containing, hard capsule.
 16. A method accordingto claim 15, wherein at least a portion of the active principle is afluid either at or immediately prior to its time of use or during itsmanufacture.
 17. A method according to claim 15 or 16 wherein at leastthe first hard capsule comprises gelatin, plasticised gelatin, hydroxypropyl methyl cellulose (HPMC), starch or agar.
 18. A method accordingto claim 15, 16 or 17, wherein at least one of the first and secondcapsules is coated or uncoated in accordance with a desired releaseprofile of active principle.
 19. A method according to any of claims 15to 18, wherein the fluid is a liquid which comprises a solution and/or asuspension of active principle.
 20. A method according to claim 19,wherein the liquid is thermosoftening.
 21. A method according to any ofclaims 15 to 20, wherein the active principle comprises a fluidsuspended solid.
 22. A method according to claim 21, wherein thefluid-suspended solid comprises a powder, a pellet, granules or anycombination thereof.
 23. A method according to claim 21 or 22 furthercomprising formulating a desired release profile of active principle andproviding the suspended solid in coated or uncoated form, such that therelease thereof accords with the desired release profile.
 24. A methodaccording to claim 23, wherein the desired release profile is determinedby a nominal or theoretical pharmaco-kinetic profile of the activeprinciple.
 25. A method according to any of claims 15 to 24, wherein atleast one of the first and second capsules contains the active principlein more than one phase.
 26. A method according to any of claims 15 to25, wherein more than one second capsule is placed within the first,hard capsule, the second capsules being arranged in parallel and/or inseries.
 27. A method according to any of claims 15 to 26 furthercomprising providing a pharmaceutical dosage form for the administrationof the same active principle in single therapies.
 28. A method accordingto any of claims 15 to 27, wherein the active principle comprises amedicinal or nutritional product.
 29. A method according to any ofclaims 15 to 28 further comprising providing an activator or co-reactantfor the active principle within the delivery device.
 30. A method ofcontrolling the pharmaco-kinetic profile of an active principlecomprising the steps of: determining a first efficacious site for activeprinciple release; placing an active principle in a first hard capsule;placing the same active principle in a second capsule within theactive-principle-containing, first hard capsule, with the activeprinciple in at least one of the first and second capsules comprising afluid (as hereinbefore defined); delivering the delivery device to thepredetermined site; and controlling the release of the active principleat the site.
 31. A method according to claim 30 further comprising:determining a second efficacious site for active principle release;delivering at least a portion of the delivery device to the second sitesubsequent to the delivery of said device to the first site; andcontrolling the release of active principle at the second site.
 32. Amethod according to claim 30 or 31, wherein the active principlecomprises a medicinal or nutritional product.
 33. A method according toclaim 30, 31 or 32, wherein said control of the release of the activeprinciple is afforded by the dissolution characteristics of at least oneof the first and second capsules.